Non-flammable insecticide composition and uses thereof

ABSTRACT

The present invention provides a safe and effective insecticide composition suitable for treating a subject infested with a parasitic anthropode or to prevent infestation by an arthropod. The insecticide composition is a foamable composition, including a first insecticide; at least one organic carrier selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 5%, or about 5% to about 10%; or about 10% to about 20%; or about 20% to about 50% by weight; about 0.1% to about 5% by weight of a surface-active agent; about 0.01% to about 5% by weight of at least one polymeric agent selected from a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and (5) a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of co-pendingU.S. patent application Ser. No. 10/532,618 filed on Dec. 22, 2005 whichis a 371 application of International Patent Application No.IB03/005527, designating the United States and filed on Oct. 24, 2003,which claims the benefit of priority under 35 U.S.C. §119(e) to U.S.patent application Ser. No. 60/429,546, filed on Nov. 29, 2002, bothentitled “Cosmetic and Pharmaceutical Foam,” and which claims thebenefit of priority under 35 USC §119(a) to Israeli Patent ApplicationNo. 152486, filed Oct. 25, 2002, all of which are hereby incorporated intheir entirety by reference.

This application is a continuation-in-part application of co-pendingU.S. patent application Ser. No. 10/911,367, filed on Aug. 4, 2004,which claims the benefit of priority under 35 U.S.C. §119(e) to U.S.Patent Application Ser. No. 60/492,385, filed on Aug. 4, 2003, bothentitled “Foam Carrier Containing Amphiphilic Copolymer Gelling Agent”and both hereby incorporated in their entirety by reference.

This application is a continuation application of and claims priority toU.S. application Ser. No. 11/481,596, filed on Jul. 6, 2006, entitledNon-Flammable Insecticide Composition and Users thereof which claims thebenefit of priority under 35 U.S.C. §119(e) to U.S. Patent ApplicationSer. No. 60/696,878, filed on Jul. 6, 2005, entitled “Non-FlammableInsecticide Composition and Uses Thereof,” which is hereby incorporatedin its entirety by reference.

BACKGROUND OF THE INVENTION

This invention relates to foamed insecticide compositions.

An insecticide is a compound used to kill or prevent the growth ofparasite arthropods, such as insects and/or arachnids and/or crustacean;or a compound used to repel or prevent infestation by parasitearthropods, such as insects and/or arachnids and/or crustacean. Commoninfestations in humans include lice and scabies.

Infestation with lice is referred to as pediculosis. Lice areectoparasites that live on the body. The 3 types of lice that parasitizehumans are Pediculus humanus capitis (head louse), Pediculus humanuscorporis (body louse), and Pthirus pubis (pubic louse).

Every year, between six and 12 million people in the United States,primarily children three to 10 years of age, are infested with headlice. Girls are at greater risk because they have more frequenthead-to-head contact. Head lice affect people across the socioeconomicspectrum.

Scabies is an infestation of the skin with the microscopic miteSarcoptes scabei. Infestation is common, found worldwide, and affectspeople of all races and social classes. Scabies spreads rapidly undercrowded conditions where there is frequent skin-to-skin contact betweenpeople, such as in hospitals, institutions, child-care facilities, andnursing homes.

Occasionally, a skin infection develops following a bite. Scratching asa result of insect bites can damage the skin and allow bacteria to getin. Infection causes redness and tenderness around the bite, which maygradually spread, and sometimes can become serious.

Resistance of insects to pesticides is commonly known. For example,resistance of lice to 1 percent permethrin has been reported in the USand elsewhere. There are two broad mechanisms by which insect pestsdevelop resistance to insecticides. They may produce large amounts ofenzymes, such as esterases which either break down the insecticidemolecule or bind to it so tightly that it cannot function (a processknown as sequestration). The second mechanism involves mutation of theinsecticide target site, such as the acetylcholinesterase enzyme in thenervous system. This effectively blocks the action of the insecticide.Both types of mechanism have been studied in various species of insect.

A common way to overcome resistance is to add a secondary active agent,which impedes that resistance mechanism. An example of such secondaryactive agent is piperony butoxide, which inhibits the ability of insectsto degrade insecticides such as pyrethrum. Another approach is to addvolatile solvents such as ethanol and propanol to the insecticideformulation.

U.S. Pat. No. 5,783,202 provides a pediculicidal mousse compositioncontaining (a) from about 0.1 to about 10% w/w of a pediculicidal agent,preferably, pyrethrin, and, optionally from about 0.5 to about 15% w/wof a synergizer therefor, such as piperonyl butoxide, (b) about 70 toabout 97% w/w of a foaming agent, which is preferably a quick breakingalcoholic foaming agent; and (c) from about 3 to about 20% w/w of anaerosol propellant.

A pediculocide mousse, which contains the active ingredients piperonylbutoxide (4%) and pyrethrum (0.33%) and the inactive ingredientscetearyl alcohol, isobutane, PEG-20 stearate, propane, propylene glycol,purified water, quaternium-52, SD Alcohol 3-C (26.5% w/w) iscommercially available under the name “RID Lice Killing Mousse” (BayerCorporation). However, this product possesses at least fourdisadvantages: (1) Irritability: due to the high alcohol content, theincidence of skin and eye irritation is high; (2) “Quick breaking”property: the foam is thermo-sensitive and breaks down rapidly at bodytemperature so that is cannot easily bespread manually throughout thescalp area; (3) Skin drying; and (4) Inflammability: 26.3% alcoholrenders the foam inflammable. A test according to European Standard prEN14851, titled “Aerosol containers—Aerosol foam flammability test”reveals that this product is inflammable.

Thus, the development of new formulations of permethrin, which willovercome these and other disadvantages, is warranted.

Furthermore, an easy to use product that addresses the frequent skin andeye irritation associated with pediculocide shampoo, cream rinses andlotions is highly desirable.

SUMMARY OF THE INVENTION

The present invention provides a safe and effective insecticidecomposition. In one aspect, the composition of the present invention issuitable for treating a subject infested with a parasiteor preventinginfestation by a parasite. In some embodiments, the parasite is anarthropod.

In one or more embodiments, the insecticide composition is a foamablecomposition, including:

(1) a first insecticide;

(2) at least one organic carrier selected from a hydrophobic organiccarrier, a polar solvent, an emollient and mixtures thereof, at aconcentration of about 2% to about 5%, or about 5% to about 10%; orabout 10% to about 20%; or about 20% to about 50% by weight;

(3) a surface-active agent;

(4) about 0.01% to about 5% by weight of at least one polymeric agentselected from a bioadhesive agent, a gelling agent, a film forming agentand a phase change agent; and

(5) a liquefied or compressed gas propellant at a concentration of about3% to about 25% by weight of the total composition.

In another aspect of the present invention, an insecticide compositionincludes:

-   -   (i) a first insecticide;    -   (ii) an organic carrier, at a concentration of about 5% to about        50%, said organic carrier containing at least one member        selected from the group of (1) a second insecticide comprising a        plant-derived oil having the ability to kill or prevent the        growth of parasite arthropods or to repel or prevent infestation        by parasite arthropods, and (2) a potent solvent; and    -   (iii) a surface-active agent.

In a further embodiment, the insecticide composition contains both (1) asecond insecticide, for example, a plant-derived oil having the abilityto kill or prevent the growth of parasite arthropods or to repel orprevent infestation by parasite arthropods, and (2) a potent solvent.

In further embodiments, the insecticide is an emulsion, for example, anoil-in-water emulsion.

In still other embodiments, a therapeutic kit provides a safe andeffective dosage of an insecticide. The kit includes an aerosolpackaging assembly including a container accommodating a pressurizedproduct, and an outlet capable of releasing the pressurized product as afoam. The pressurized product is any of the foamable compositionsdescribed herein.

Water and optional ingredients are added to complete the total mass to100%. All % values are provided on a weight (w/w) basis. Upon releasefrom an aerosol container, the foamable composition forms an expandedfoam suitable for topical administration.

DETAILED DESCRIPTION OF THE INVENTION

The foamable insecticide composition is contained in an aerosolcontainer. Upon release from an aerosol container, the foamablecomposition forms an expanded foam suitable for the treatment of bodiesand surfaces.

According to one or more embodiments, the foamable composition issubstantially alcohol-free, i.e., free of short chain alcohols. Shortchain alcohols, having up to 5 carbon atoms in their carbon chainskeleton and one hydroxyl group, such as ethanol, propanol, isopropanol,butanol, iso-butanol, t-butanol and pentanol, are considered lessdesirable solvents or polar solvents due to their skin-irritatingeffect. This disadvantage is particularly meaningful in the case of aninsecticide treatment, which is often directed to sensitive and damagedskin and mucosal tissues. Thus, in one or more embodiments, thecomposition is substantially alcohol-free and includes less than about5% final concentration of lower alcohols, preferably less than about 2%,more preferably less than about 1%.

Insecticide

In the context of one or more embodiments of the present invention, aninsecticide is a compound used to kill or prevent the growth of parasitearthropods, such as insects, arachnids and crustaceans, or a compoundused to repel or prevent infestation by these parasite arthropods.

In one or more embodiments, the insecticide is an antibioticinsecticide. Examples of antibiotic insecticides include allosamidin,thuringiensin, spinosad, avermectin insecticides, such as abamectin,doramectin, emamectin, eprinomectin, ivermectin and selamectin,milbemycin insecticides, such as lepimectin, milbemectin, milbemycinoxime and moxidectin, and arsenical insecticides.

In one or more embodiments, the insecticide is a botanical insecticide,such as anabasine, azadirachtin, d-limonene, nicotine, pyrethrins,cinerins, jasmolin, quassia, rotenone, ryania and sabadilla.

In one or more embodiments, the insecticide is a carbamate insecticide.Examples of carbamate insecticides include bendiocarb, carbaryl,benzofuranyl methylcarbamate insecticides, such as benfuracarb,carbofuran, carbosulfan, decarbofuran and furathiocarb,dimethylcarbamate insecticides, such as dimetan, dimetilan, hyquincarband pirimicarb, oxime carbamate insecticides, such as alanycarb,aldicarb, aldoxycarb, butocarboxim, butoxycarboxim, methomyl,nitrilacarb, oxamyl, tazimcarb, thiocarboxime, thiodicarb and thiofanox,and phenyl methylcarbamate insecticides, such as allyxycarb, aminocarb,bufencarb, butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb,ethiofencarb, fenethacarb, fenobucarb, isoprocarb, methiocarb,metolcarb, mexacarbate, promacyl, promecarb, propoxur, trimethacarb andxylylcarb.

In one or more embodiments, the insecticide is a dinitrophenolinsecticides. Examples of dinitrophenol insecticides include dinex,dinopropand dinosam.

In one or more embodiments, the insecticide is a fluorine insecticide,such as barium hexafluorosilicate, cryolite, sodium fluoride, sodiumhexafluorosilicate and sulfluramid.

In one or more embodiments, the insecticide is a formamidineinsecticide, such as amitraz, chlordimeform, formetanate andformparanate.

In one or more embodiments, the insecticide is an insect growthregulator. Examples of insect growth regulators include chitin synthesisinhibitors, such as bistrifluoron, buprofezin, chlorfluazuron,cyromazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron,lufenuron, novaluron, noviflumuron, penfluoron, teflubenzuron andtriflumuron, juvenile hormone mimics, such as epofenonane, fenoxycarb,hydroprene, kinoprene, methoprene, pyriproxyfen and triprene, juvenilehormones, moulting hormone agonists, such as chromafenozide,halofenozide, methoxyfenozide and tebufenozide, moulting hormones, suchas α-ecdysone and ecdysterone, moulting inhibitors, such as diofenolan,precocenes, and dicyclanil.

In one or more embodiments, the insecticide is a nereistoxin analogueinsecticide, such as bensultap, cartap, thiocyclam and thiosultap.

In one or more embodiments, the insecticide is a nicotinoid insecticide.Examples of nicotinide insecticides include flonicamid, nitroguanidineinsecticides, such as clothianidin, dinotefuran, imidacloprid andthiamethoxam, nitromethylene insecticides, such as nitenpyram andnithiazine, and pyridylmethylamine insecticides, such as acetamiprid,imidacloprid, nitenpyram and thiacloprid.

In one or more embodiments, the insecticide is an organochlorineinsecticide. Examples of organochlorine insecticides include bromo-DDT,camphechlor, DDT, lindane, methoxychlor, pentachlorophenol, cyclodieneinsecticides, such as aldrin, bromocyclen, chlorbicyclen, chlordane,chlordecone, dieldrin, dilor, endosulfan, endrin, heptachlor, isobenzan,isodrin, kelevan and mirex.

In one or more embodiments, the insecticide is an organophosphorusinsecticide. Examples of organophosphorus insecticides includeorganophosphate insecticides such as bromfenvinfos, chlorfenvinphos,crotoxyphos, dichlorvos, dicrotophos, dimethylvinphos, fospirate,heptenophos, methocrotophos, mevinphos, monocrotophos, naftalofos,phosphamidon, propaphos and tetrachlorvinphos, organothiophosphateinsecticides, such as dioxabenzofos, fosmethilan, phenthoate, acethion,amiton, cadusafos, chlorethoxyfos, chlormephos, demephion, demephion,demeton, disulfoton, ethion, ethoprophos, isothioate, malathion,methacrifos, oxydemeton-methyl, oxydeprofos, oxydisulfoton, phorate,sulfotep, terbufos and thiometon, aliphatic amide organothiophosphateinsecticides, such as amidithion, cyanthoate, dimethoate,ethoate-methyl, formothion, mecarbam, omethoate, prothoate, sophamideand vamidothion, oxime organothiophosphate insecticides, such aschlorphoxim, phoxim and phoxim-methyl, heterocyclic organothiophosphateinsecticides, such as azamethiphos, coumaphos, coumithoate, dioxathion,endothion, menazon, morphothion, phosalone, pyraclofos, pyridaphenthionand quinothion, benzothiopyran organothiophosphate insecticides, such asdithicrofos and thicrofos, benzotriazine organothiophosphateinsecticides, such as azinphos-ethyl and azinphos-methyl, isoindoleorganothiophosphate insecticides, such as dialifos and phosmet,isoxazole organothiophosphate insecticides, such as isoxathion andzolaprofos, pyrazolopyrimidine organothiophosphate insecticides, such aschlorprazophos and pyrazophos; pyridine organothiophosphateinsecticides, such as chlorpyrifos and chlorpyrifos-methyl, pyrimidineorganothiophosphate insecticides, such as butathiofos, diazinon,etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl, primidophos,pyrimitate and tebupirimfos, quinoxaline organothiophosphateinsecticides, such as quinalphos and quinalphos-methyl, thiadiazoleorganothiophosphate insecticides, such as athidathion, lythidathion,methidathion and prothidathion, triazole organothiophosphateinsecticides, such as isazofos and triazophos, phenylorganothiophosphate insecticides, such as azothoate, bromophos,bromophos-ethyl, carbophenothion, chlorthiophos, cyanophos, cythioate,dicapthon, dichlofenthion, etaphos, famphur, fenchlorphos, fenitrothion,fensulfothion, fenthion, fenthion-ethyl, heterophos, jodfenphos,mesulfenfos, parathion, parathion-methyl, phenkapton, phosnichlor,profenofos, prothiofos, sulprofos, temephos, trichlormetaphos-3 andtrifenofos, phosphonate insecticides, such as butonate and trichlorfon,phosphonothioate insecticides such as mecarphon, phenylethylphosphonothioate insecticides, such as fonofos and trichloronat,phenyl phenylphosphonothioate insecticides, such as cyanofenphos, EPNand leptophos, phosphoramidate insecticides, such as crufomate,fenamiphos, fosthietan, mephosfolan, phosfolan and pirimetaphos,phosphoramidothioate insecticides, such as acephate, isocarbophos,isofenphos, methamidophos and propetamphos, and phosphorodiamideinsecticides, such as dimefox, mazidox, mipafox and schradan.

In one or more embodiments, the insecticide is an oxadiazineinsecticide, such as indoxacarb.

In one or more embodiments, the insecticide is a phthalimideinsecticide, such as dialifos, phosmet and tetramethrin.

In one or more embodiments, the insecticide is a pyrazole insecticide,such as acetoprole, ethiprole, fipronil, pyrafluprole, pyriprole,tebufenpyrad, tolfenpyrad and vaniliprole.

In one or more embodiments, the insecticide is a pyrethroid insecticide.Examples of pyrethroid insecticides include pyrethroid esterinsecticides, such as acrinathrin, allethrin, bioallethrin, barthrin,bifenthrin, bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin,beta-cyfluthrin, cyhalothrin, cypermethrin, alpha-cypermethrin,beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin,deltamethrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin,fenpirithrin, fenpropathrin, fenvalerate, esfenvalerate, flucythrinate,fluvalinate, furethrin, imiprothrin, metofluthrin, permethrin,biopermethrin, transpermethrin, phenothrin, prallethrin, profluthrin,pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin,terallethrin, tetramethrin, tralomethrin and transfluthrin, andpyrethroid ether insecticides, such as etofenprox, flufenprox,halfenprox, protrifenbute and silafluofen.

In one or more embodiments, the insecticide is a pyrimidinamineinsecticide, such as flufenerim and pyrimidifen.

In one or more embodiments, the insecticide is a pyrrole insecticide,such as chlorfenapyr.

In one or more embodiments, the insecticide is a tetronic acidinsecticide, such as spiromesifen and spirotetramat.

In one or more embodiments, the insecticide is a thiourea insecticide,such as diafenthiuron.

In one or more embodiments, the insecticide is a urea insecticide, suchas flucofuron and sulcofuron.

Yet, in additional embodiments, the insecticide is an unclassifiedinsecticide, such as closantel, crotamiton, fenazaflor, fenoxacrim,flubendiamide, hydramethylnon, isoprothiolane, malonoben, metaflumizone,metoxadiazone, nifluridide, pyridaben, pyridalyl, rafoxanide,triarathene and triazamate.

The above listed insecticides, as well as others not listed, aresuitable for use in the composition of the present invention. It ispreferred to use insecticides that are approved by the FDA or otherhealth authorities for the treatment of animals and humans.

Non-limiting examples of approved insecticides includehexachlorobenzene, carbamate, naturally occurring pyrethroids,permethrin, allethrin, bioalethrin, phenothrin, malathion and piperonylbutoxide. In a preferred embodiment of the present invention theinsecticide is selected from the group consisting of hexachlorobenzene,carbamate, naturally occurring pyrethroids, permethrin, allethrin,bioalethrin, phenothrin, malathion and piperonyl butoxide.

In one or more embodiments, the insecticide is a naturally occurringinsecticide compound. As used herein, the term “naturally-occurringinsecticide” includes all insecticides that are obtained, derived orextracted from plant or vertebrate sources.

In the context of the present invention, an agent that kills orotherwise affects parasites, such as protozoa is also termed aninsecticide (for the purpose of this application terminology only).Exemplary antiparasites are mebendazole, thiabendazole, metronidazole,and praziquantel.

Mixtures of these insecticides may also be employed according to thepresent invention.

The insecticide is included in the composition of the present inventionin a concentration that provides a desirable ratio between the efficacyand safety. Typically, insecticides are included in the composition in aconcentration between about 0.05% and about 12% by weight, depending ontheir potency against the parasitic arthropod to be eradicated. In someembodiments, the concentration is between about 0.5% and about 2% byweight; in other embodiment the concentration is between about 2% andabout 5% by weight; and in other embodiments the concentration isbetween about 5% and about 12% by weight.

In one or more embodiments, the insecticide is encapsulated inparticles, microparticles, nanoparticles, microcapsules, spheres,microspheres, nanocapsules, nanospheres, liposomes, niosomes, polymermatrix, nanocrystals or microsponges, and may be manufactured accordingto known methods.

Organic Carrier

The foamable composition of the present invention can be an emulsion, ormicroemulsion, including an aqueous phase and an organic carrier phase.The organic carrier is selected from a hydrophobic organic carrier (alsotermed herein “hydrophobic solvent”), an emollient, a solvent, and amixture thereof.

A “hydrophobic organic carrier” as used herein refers to a materialhaving solubility in distilled water at ambient temperature of less thanabout 1 gm per 100 mL, more preferable less than about 0.5 gm per 100mL, and most preferably less than about 0.1 gm per 100 mL. It is liquidat ambient temperature. The identification of a hydrophobic organiccarrier or “hydrophobic solvent”, as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a hydrophobic carrier inthe foamable compositions described herein.

In one or more embodiments, the hydrophobic organic carrier is an oil,such as mineral oil. According to one or more embodiments, thehydrophobic solvent is a liquid oil originating from vegetable, marineor animal sources. Suitable liquid oil includes saturated, unsaturatedor polyunsaturated oils. Another class of hydrophobic solvents is theessential oils. Silicone oils also may be used and are desirable due totheir known skin protective and occlusive properties.

A further class of organic carriers includes “emollients” that have asoftening or soothing effect, especially when applied to body areas,such as the skin and mucosal surfaces. Emollients are not necessarilyhydrophobic. Examples of suitable emollients include hexyleneglycol,propylene glycol, isostearic acid derivatives, isopropyl palmitate,isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate,maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyltrimethicone, glyceryl oleate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, triisocetylcitrate, octyl dodecanol, sucrose esters of fatty acids, octylhydroxystearate and mixtures thereof.

In an embodiment of the present invention, the organic carrier is apolypropylene glycol alkyl ether (PPG alkyl ether). PPG alkyl ethers areliquid, water-insoluble propoxylated fatty alcohols, having themolecular formula of RO(CH₂CHOCH₃)_(n), wherein “R” is astraight-chained or branched C₄ to C₂₂ alkyl group; and “n” is in therange between 4 and about 50. They are organic liquids that function asskin-conditioning agent in pharmaceutical and cosmetic formulations.Non-limiting exemplary PPG alkyl ethers include PPG stearyl ethers andPPG butyl ether. Preferred PPG alky ethers according to the presentinvention include PPG-15 stearyl ether, PPG-2 butyl ether, PPG-9-13butyl ether and PPG-40 butyl ether.

According to a preferred embodiment, the organic carrier does notcontain petrolatum, which is also referred to as “white petrolatum”anord Vaseline”. Petrolatum often forms an impermeable occlusivebarrier, so that metabolic products and excreta from damaged tissue arenot easily removed or drained away. Furthermore, it is difficult for theactive drug dissolved in the carrier to pass through the whitepetrolatum barrier layer into the treated tissue, so the efficacy of thedrug is reduced. An additional disadvantage of petroleum jelly-basedproducts relates to the greasy feeling left following their topicalapplication onto the skin, mucosal membranes and wounds causinginconvenience to the user, thereby decreasing treatment compliance.

In one or more embodiments, the organic carrier contains a plant-derivedoil, which possesses insecticide properties, i.e., a plant derived oilthat has the ability to kill or prevent the growth of parasitearthropods or to repel or prevent infestation by parasite arthropods(herein referred to as a “second hydrophobic insecticide” or “plantderived insecticide”).

Examples of plant-derived insecticides include but are not limited tothe oils of anise, bergemont, canola, cassia, catnip, cedarwood,citronella, clove, eucalyptus, garlic, ginger, grapefruit, jojova,lavender, lavandin, lemon, lime, orange, peppermint, rosemary, sage,spearmint, star anise, tea tree, tangerine, thyme and white clover.

In one or more embodiments, the “second insecticide” agent is an insectrepellent. In one or more embodiment, the insect repellant is a chemicalinsect repellent, such as diethyl toluamide (DEET). In one or moreembodiments, the insect repellent is a naturally-derived Insectrepellent.

In one or more embodiments, the insect repellent is repellents thatinclude terpenoid compounds, as described in U.S. Pat. No. 5,411,992,including:

(1) Terpenoid-alcohol or terpene-ols are terpenoids which have at leastone hydroxyl group. Examples of terpene-ols include: C₁₀H₁₆O compounds,perillyl alcohol, carveol, myrtenol, and cis-verbenol; C₁₀H₁₈Ocompounds, myrtanol, iso-pinocampheol, dihydrocarveol, isopulegol,terpineol, terpinen-4-ol, nerol, geraniol, and linalool, and C₁₀H₂₀0compounds, menthol, beta-citronellol, and dihydro-myrcenol.

(2) Terpenoid-esters are terpenoids, which have at least one ester groupwhich is the product of the bonding of the hydroxyl group of aterpene-ol with an aliphatic carboxylic acid that can contain functionalgroups such as the hydroxyl or amine on the aliphatic chain. Examples ofsuitable aliphatic carboxylic acids include acetic acid, propionic acid,lactic acid, and various amino acids. Examples of terpenoid-estersinclude carvyl acetate, carvyl propionate, and menthyl lactate.

(3) Essential oils which contain terpenoids and perfumes which containterpenoids. Non-limiting examples of essential oils which have highcontent of terpene-ols and esters include bergamot (62% terpenoids);sage (>50% terpenoids); styrax (>50% terpenoids); peppermint (>50%terpenoids); and pine Siberian (75% terpenoids).

Combining a first insecticide and a second insecticide having differentmechanisms of action provides an enhanced and conceivably a synergisticeffect against the parasitic arthropods.

Potent Solvent

In one or more embodiments, the organic carrier contains at least onesolvent having a high solubilization capacity, termed herein a “potentsolvent”. In the context of the present invention, a potent solvent is asolvent, other than a short chain alcohol or water, that solubilizes thefirst and/or second insecticide.

In one or more embodiments, the potent solvent is selected from thegroup consisting of a polyol, propylene glycol, hexylene glycol,butanediol, diethylene glycol, benzyl alcohol, terpenes, di-terpenes,tri-terpenes, limonene, terpene-ol, dioxolane, dimethylformanide,dimethyl solfoxide (DMSO), methyl dodecyl sulfoxide, ethyl oleate, ethylcaprylate, diisopropyl adipate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, dimethylacetamide,azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane,isosorbide derivatives, dimethyl isosorbide, glycofurol andethoxydiglycol (transcutol) and mixtures thereof in any proportion.

Combining a first insecticide and a potent solvent increase penetrationof the insecticide to its target site of action and dissolves thecuticle of the arthropodor the outer surface of the nits, therebyproviding an enhanced and conceivably a synergistic effect against theparasitic arthropods.

In one or more embodiments, the organic carrier contains both a secondinsecticide and a potent solvent. The combination of a firstinsecticide, a second insecticide and a potent solvent in combinationprovides an exceptionally effective product for the treatment ofparasitic arthropods, as demonstrated in the examples herein.

Polymeric Agent

The polymeric agent serves to stabilize the foam composition and tocontrol drug residence in the target organ. Exemplary polymeric agentsare classified below in a non-limiting manner. In certain cases, a givenpolymer can belong to more than one of the classes provided below.

In one or more embodiments, the polymeric agent includes at least onegelling agent. A gelling agent controls the residence of a therapeuticcomposition in the target site of treatment by increasing the viscosityof the composition, thereby limiting the rate of its clearance from thesite. Many gelling agents are known in the art to possess mucoadhesiveproperties.

The gelling agent can be a natural gelling agent, a synthetic gellingagent and an inorganic gelling agent. Exemplary gelling agents that canbe used in accordance with one or more embodiments of the presentinvention include, for example, naturally-occurring polymeric materials,such as locust bean gum, sodium alginate, sodium caseinate, egg albumin,gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seedextract, tragacanth gum, guar gum, starch, chemically modified starchesand the like, semi-synthetic polymeric materials such as celluloseethers (e.g. hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxypropylmethyl cellulose,hydroxyethylcarboxymethylcellulose, carboxymethylcellulose andcarboxymethylhydroxyethylcellulose), guar gum, hydroxypropyl guar gum,soluble starch, cationic celluloses, cationic guars, and the like, andsynthetic polymeric materials, such as carboxyvinyl polymers,polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers,polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinylchloride polymers, polyvinylidene chloride polymers and the like.Mixtures of the above compounds are contemplated.

Further exemplary gelling agents include the acrylic acid/ethyl acrylatecopolymers and the carboxyvinyl polymers, which consist essentially of acolloidal water-soluble polyalkenyl polyether crosslinked polymer ofacrylic acid crosslinked with a crosslinking agent such as polyallylsucrose or polyallyl pentaerythritol. Examples include Carbopol® 934,Carbopol® 940, Carbopol® 950, Carbopol® 980, Carbopol® 951 and Carbopol®981.

The polymeric agent can be an inorganic gelling agent, such as siliconedioxide (fumed silica).

In an embodiment of the present invention, the polymeric agent includesat least one mucoadhesive or bioadhesive agent. Mucoadhesive/bioadhesionhas been defined as the attachment of synthetic or biologicalmacromolecules to a biological tissue. Mucoadhesive agents are a classof polymeric biomaterials that exhibit the basic characteristic of ahydrogel, i.e. swell by absorbing water and interacting by means ofadhesion with the mucous that covers epithelia. Compositions accordingto one or more embodiments of the present invention may contain amucoadhesive macromolecule or polymer in an amount sufficient to conferbioadhesive properties. The bioadhesive macromolecule enhances thedelivery of biologically active agents on or through the target surface.The mucoadhesive macromolecule may be selected from acidic syntheticpolymers, preferably having at least one acidic group per four repeatingor monomeric subunit moieties, such as poly(acrylic)- and/orpoly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinylether/maleic anhydride) copolymer, and their mixtures and copolymers;acidic synthetically modified natural polymers, such ascarboxymethylcellulose (CMC); neutral synthetically modified naturalpolymers, such as (hydroxypropyl)methylcellulose; basic amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth,and karaya gum; and neutral synthetic polymers, such as polyvinylalcohol or their mixtures. An additional group of mucoadhesive polymersincludes natural and chemically modified cyclodextrin, especiallyhydroxypropyl-β-cyclodextrin. Such polymers may be present as freeacids, bases, or salts, usually in a final concentration of about 0.01%to about 0.5% by weight. Many mucoadhesive agents are known in the artto also possess gelling properties.

In one or more embodiments, the polymeric agent includes at least onefilm forming polymer. The film forming component may include at leastone water-insoluble alkyl cellulose or hydroxyalkyl cellulose. Exemplaryalkyl cellulose or hydroxyalkyl cellulose polymers include ethylcellulose, propyl cellulose, butyl cellulose, cellulose acetate,hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethylcellulose, alone or in combination. In addition, a plasticizer or across linking agent may be used to modify the polymer's characteristics.For example, esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asoleic and myristyl acid may be used in combination with the cellulosederivative.

In one or more embodiments, the polymeric agent includes at least onephase change polymer, which alters the composition behavior fromfluid-like prior to administration to solid-like upon contact with thetarget mucosal surface. Such phase change results from external stimuli,such as changes in temperature or pH and exposure to specific ions(e.g., Ca²⁺). Non-limiting examples of phase change polymers includepoly(N-isopropylamide) and Poloxamer 407®.

The polymeric agent is present in an amount in the range of about 0.01%to about 5.0% by weight of the foam composition. In one or moreembodiments, it is typically less than about 1 wt % of the foamablecomposition.

Surface Active Agent

Surface-active agents (also termed “surfactants”) include any agentlinking oil and water in the composition, in the form of emulsion. Asurfactant's hydrophilic/lipophilic balance (HLB) describes theemulsifier's affinity toward water or oil. The HLB scale ranges from 1(totally lipophilic) to 20 (totally hydrophilic), with 10 representingan equal balance of both characteristics. Lipophilic emulsifiers formwater-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water(o/w) emulsions. The HLB of a blend of two emulsifiers equals the weightfraction of emulsifier A times its HLB value plus the weight fraction ofemulsifier B times its HLB value (weighted average). The surface activeagent according to the present invention has an HLB value, suitable forstabilizing an emulsion comprising the aqueous phase and the organiccarrier of the composition.

According to one or more embodiments of the present invention, thesurface-active agent has a hydrophilic lipophilic balance (HLB) betweenabout 9 and about 14, which is the required HLB (the HLB required tostabilize an O/W emulsion of a given oil) of most oils and hydrophobicsolvents. Thus, in one or more embodiments, the composition contains asingle surface active agent having an HLB value between about 9 and 14,and in one or more embodiments, the composition contains more than onesurface active agent and the weighted average of their HLB values isbetween about 9 and about 14. Yet, in other embodiments, when a water inoil emulsion is desirable, the composition contains one or more surfaceactive agents, having an HLB value between about 2 and about 9.

The surface-active agent is selected from anionic, cationic, nonionic,zwitterionic, amphoteric and ampholytic surfactants, as well as mixturesof these surfactants. Such surfactants are well known to those skilledin the therapeutic and cosmetic formulation art. Nonlimiting examples ofpossible surfactants include polysorbates, such as polyoxyethylene (20)sorbitan monostearate (Tween 60) and poly(oxyethylene) (20) sorbitanmonooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters, suchas Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkylylethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene)palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycolcetyl ether, brij 38, brij 52, brij 56 and brij W1; sucrose esters,partial esters of sorbitol and its anhydrides, such as sorbitanmonolaurate and sorbitan monolaurate; mono or diglycerides,isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyltaurate, sodium lauryl sulfate, triethanolamine lauryl sulfate andbetaines.

In one or more embodiments of the present invention, the surface-activeagent includes at least one non-ionic surfactant. Ionic surfactants areknown to be irritants. Therefore, non-ionic surfactants are preferred inapplications including sensitive tissue such as found in most mucosaltissues, especially when they are infected or inflamed. We havesurprisingly found that non-ionic surfactants alone provide foams ofexcellent quality, i.e. a score of “E” according to the grading scalediscussed herein below.

In one or more embodiments, the surface active agent includes a mixtureof at least one non-ionic surfactant and at least one ionic surfactantin a ratio in the range of about 100:1 to 6:1. In one or moreembodiments, the non-ionic to ionic surfactant ratio is greater thanabout 6:1, or greater than about 8:1; or greater than about 14:1, orgreater than about 16:1, or greater than about 20:1.

In one or more embodiments of the present invention, a combination of anon-ionic surfactant and an ionic surfactant (such as sodium laurylsulphate and cocamidopropylbetaine) is employed, at a ratio of between1:1 and 20:1, or at a ratio of 4:1 to 10:1. The resultant foam has a lowspecific gravity, e.g., less than 0.1 g/ml.

The stability of the composition is especially pronounced when acombination of at least one non-ionic surfactant having HLB of less than9 and at least one non-ionic surfactant having HLB of equal or more than9 is employed. The ratio between the at least one non-ionic surfactanthaving HLB of less than 9 and the at least one non-ionic surfactanthaving HLB of equal or more than 9, is between 1:8 and 8:1, or at aratio of 4:1 to 1:4. The resultant HLB of such a blend of at least twoemulsifiers is between about 9 and about 14.

Thus, in an exemplary embodiment, a combination of at least onenon-ionic surfactant having HLB of less than 9 and at least onenon-ionic surfactant having HLB of equal or more than 9 is employed, ata ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein theHLB of the combination of emulsifiers is between about 9 and about 14.

In one or more embodiments of the present invention, the surface-activeagent includes mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), prepared from sucrose and esters of fatty acids or byextraction from sucro-glycerides. Suitable sucrose esters include thosehaving high monoester content, which have higher HLB values.

The total surface active agent is in the range of about 0.1 to about 5%of the composition, and is occasionally less than about 2% or less thanabout 1%.

Foam Adjuvant

Optionally, a therapeutically effective foam adjuvant is included in thefoamable compositions of the present invention to increase the foamingcapacity of surfactants and/or to stabilize the foam. In one or moreembodiments of the present invention, the foam adjuvant agent includesfatty alcohols having 15 or more carbons in their carbon chain, such ascetyl alcohol and stearyl alcohol (or mixtures thereof). Other examplesof fatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22),1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50). Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are especially well suited as foam adjuvant agents. Theamount of the fatty alcohol required to support the foam system isinversely related to the length of its carbon chains. Foam adjuvants, asdefined herein are also useful in facilitating improved spreadabilityand absorption of the composition.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.As for fatty alcohols, the amount of fatty acids required to support thefoam system is inversely related to the length of its carbon chain.

In one or more embodiments, a combination of a fatty acid and a fattyester is employed.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay be saturated or unsaturated, branched or unbranched, or hydroxylatedor unhydroxylated. The fatty alcohol or the fatty acid may have at leastone double bond. A further class of foam adjuvant agent includes abranched fatty alcohol or fatty acid. The carbon chain of the fatty acidor fatty alcohol also can be substituted with a hydroxyl group, such as12-hydroxy stearic acid.

Fatty alcohols and fatty acids useful in one or more compositions of thepresent invention may possess therapeutic properties. Long chainsaturated and mono unsaturated fatty alcohols, e.g., stearyl alcohol,erucyl alcohol, arachidyl alcohol and behenyl alcohol (docosanol) havebeen reported to possess antiviral, antiinfective, antiproliferative andantiinflammatory properties (see, U.S. Pat. No. 4,874,794). Longer chainfatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol,octacosanol, triacontanol, etc., are also known for their metabolismmodifying properties and tissue energizing properties. Long chain fattyacids have also been reported to possess anti-infective characteristics.

Additional Therapeutic Agent

Several conditions involve a combination of etiological factors, some ofwhich are related to the arthropod or another parasite infestation (thatcan be affected by an insecticide); and other etiological factors thatrequire an additional therapeutic modality. For example, pediculosis mayinvolve lice infection as well as secondary infection or inflammation,and therefore combined treatment with an insecticide and ananti-inflammatory agent or an antibiotic agent would be beneficial.Likewise, rosacea, which involves a parasite infection, inflammation andtelangiectasia, can benefit from treatment with a combination ofmetronidazole and an additional therapeutic agent, selected from thegroup consisting of an anti-inflammatory agent, an immunomodulator, ananti-pruritic agent and a vasoconstrictor. Hence, in many cases, theinclusion of an additional therapeutic agent in the composition of thepresent invention, contributes to the clinical activity of theinsecticide. Thus, in one or more embodiments, the composition furtherincludes at least one additional therapeutic agent, in a therapeuticallyeffective concentration.

In one or more embodiments, the at least one additional therapeuticagent is selected from the group consisting of a steroidalantiinflammatory agent, a nonsteroidal anti-inflammatory drug, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, an antibiotic agent, an antifungal agent, an antiviralagent, an antiparasitic agent, a vasoactive agent, a vasoconstrictor, avasodilator, vitamin A, a vitamin A derivative, vitamin B, a vitamin Bderivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin Dderivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin Fderivative, vitamin K, a vitamin K derivative, a wound healing agent, adisinfectant, an anesthetic, an antiallergic agent, an alpha hydroxylacid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, apeptide, a neuropeptide, a allergen, an immunogenic substance, ahaptene, an oxidizing agent, an antioxidant, a dicarboxylic acid,azelaic acid, sebacic acid, adipic acid, fumaric acid, an insecticide,an antiproliferative agent, an anticancer agent, a photodynamic therapyagent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g.,titanium dioxide, zinc oxide, zirconium oxide, iron oxide), siliconeoxide, an anti wrinkle agent, a skin whitening agent, a skin protectiveagent, a masking agent, an anti-wart agent, a refatting agent, alubricating agent and mixtures thereof.

The composition of the present invention may further optionally includea variety of formulation excipients, which are added in order tofine-tune the consistency of the formulation, protect the formulationcomponents from degradation and oxidation and modify their consistency.Such excipients may be selected, for example, from stabilizing agents,antioxidants, humectants, preservatives, colorant and odorant agents andother formulation components, used in the art of formulation.

Propellant

Aerosol propellants are used to generate and administer the foamablecomposition as a foam. The total composition including propellant,foamable compositions and optional ingredients is referred to as thefoamable carrier. The propellant makes up about 3% to about 25 wt % ofthe foamable carrier. Examples of suitable propellants include volatilehydrocarbons such as butane, propane, isobutane or mixtures thereof,chloro-fluoro carbons (CMCs) non-ozone-depleting and fluorocarbonpropellants, such as 1,1,1,2tetrafluorethane and1,1,1,2,3,3,3heptafluoropropane.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamcarrier according to one or more embodiments of the present invention isvery easy to use. When applied onto the afflicted body surface ofmammals, i.e., humans or animals, it is in a foam state, allowing freeapplication without spillage. Upon further application of a mechanicalforce, e.g., by rubbing the composition onto the body surface, it freelyspreads on the surface and is rapidly absorbed.

The foam composition of the present invention creates a stable emulsionhaving an acceptable shelf-life of at least one year, or at least twoyears at ambient temperature. Plant-derived oils, potent solvents andhydrocarbon propellants, which are a mixture of low molecular weighthydrocarbons, tend to impair the stability of emulsions. It has beenobserved, however, that emulsion compositions according to the presentinvention are surprisingly stable. Following accelerated stabilitystudies, they demonstrate desirable texture; they form fine bubblestructures that do not break immediately upon contact with a surface,spread easily on the treated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam.

The foam of the present invention has several advantages, when comparedwith hydroalcoholic foam compositions, such as described in U.S. Pat.No. 5,783,202:

-   -   (1) Breakability. The foam of the present invention is thermally        stable. Unlike hydroalcoholic foam compositions the foam of the        present invention is not “quick breaking”, i.e., it does not        readily collapse upon exposure to body temperature environment.        Sheer-force breakability of the foam is clearly advantageous        over thermally-induced breakability, since it allows comfortable        application and well directed administration to the target area.    -   (2) Irritability. The insecticide composition of the present        invention are non-irritant, as revealed in clinical trials,        unlike the high incidence of skin and eye irritation caused by        the hydroalcoholic foam.    -   (3) Skin drying. Alcohol is known to dry the skin and impair the        integrity of the skin barrier. By contrast, the insecticide        composition of the present invention is an emulsion, which        provides skin refatting and skin barrier building effects.    -   (4) Inflammability. Alcohol renders the foam inflammable. A test        according to European Standard prEN 14851, titled “Aerosol        containers—Aerosol foam flammability test” revealed that        compositions according to the present invention are        non-inflammable, while the hydroalcoholic foam was inflammable.

In terms of usability, the foamable composition is most advantageous, asrevealed by clinical trials:

(i) Ease of Application.

-   -   Due to the nature a foam product, Foamix Permethrin 1% Foam was        found easier to use in comparison with other products available        in the market.    -   When foam is released it expands in the hair and reaches every        spot where lice can be found. This advantage is particularly        meaningful in regards to such difficult to access areas as in        the neck and behind the ears.    -   Using the product with applicator attached to foam container        directly onto the scalp under the hair is very convenient.

(ii) The Foam is Drip-Free

-   -   The foam is not liquid and therefore is not leaking when        applied.    -   This allows precise application, without the product being        spread on clothes or other parts of the body.    -   Not a single case of contact with eyes was recorded throughout        the study. (It should be noted that the issue of contact with        eyes is a common problem when treating with shampoo, lotion and        spray which usually cause eye irritation and burning.)

(iii) Patients' Response

-   -   Throughout the study it was evident that children enjoy being        treated with foam and therefore do not resist the therapy.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, foams have specific gravity ofless than 0.12 g/mL or less than 0.05 g/mL.

Fields of Applications

The present invention provides safe and effective insecticidecompositions, suitable to treat any surface or body, infested with anparasitic anthropode, or to prevent infestation by an arthropod. In oneor more embodiments, the insecticide composition can be used to kill orprevent the growth of parasite arthropods, such as insects and/orarachnids and/or crustacean. In one or more embodiments, the insecticidecomposition can be used to repel parasite arthropods or preventinfestation by parasite arthropods.

According to one or more embodiments of the present invention, theinsecticide composition is intended for administration to an animal or ahuman subject. In one or more embodiments, the composition is intendedto treat the skin, a body surface, a body cavity or a mucosal surface,e.g., the mucosa of the nose, mouth, eye, ear, respiratory system,vagina or rectum.

In other embodiments, the insecticide composition is intended for thetreatment of plants, infested by arthropods.

Yet, in additional embodiments, the insecticide composition of bodies orsurfaces other than animal, human or botanical subjects.

The insecticide compositions of the present invention are intended forthe treatment of infestation by arthropods, including insects, arachnidsand crustaceans. Exemplary arthropods to be treated by the insecticidecompositions of the present invention are lice and blowfly larvae, bugs,fleas, gnats, ticks mites, chiggers, punkies, copepods, isopods andbarnacles.

The insecticide compositions of the present invention are intended forthe prevention of an insect-transmitted disease, such as typhus, Lymedisease, trench fever, leishmeniasis, malaria and relapsing fever.

The following examples exemplify the therapeutic compositions andpharmacological compositions and methods described herein. The examplesare for the purposes of illustration only and are not intended to belimiting of the invention.

Example 1

This example describes a foamable insecticide composition containingpermethrin (1% or 5%), or malathion (0.5%). The following compositionswere prepared by blending the listed ingredients.

Foam A Foam B Foam C % w/w % w/w % w/w Permethrin (first insecticide)1.00 5.00 Malathion (first insecticide) 0.50 Mineral oil 5.60 5.60 5.60Isopropyl myristate 5.60 5.60 5.60 Glyceryl monostearate 0.45 0.45 0.45Xanthan gum 0.25 0.25 0.25 Methocel K100M 0.25 0.25 0.25 Polysorbate 800.85 0.85 0.85 PEG-40 stearate 2.50 2.50 2.50 Sodium lauryl sulphate0.40 0.40 0.40 Preservative 0.25 0.25 0.25 TEA to pH 5.5 to pH 5.5 to pH5.5 Propane/Butane 8.00 8.00 8.00 Purified water to 100.00 to 100.00 to100.00

Example 2

This example describes a foamable insecticide composition containingpermethrin (1%), malathion (0.5%) or pyrethrum extract (0.33%)+piperonylbutoxide (4%), as “first insecticide” and diisopropyl adipate anddimethyl isosorbide as potent solvents.

Foam D Foam E Foam F % w/w % w/w % w/w Permethrin (first insecticide)1.00 Malathion (first insecticide) 0.50 Pyrethrum extract (firstinsecticide) 0.33 Piperonyl butoxide (first insecticide) 4.00Diisopropyl adipate (potent solvent) 3.00 3.00 3.00 Dimethyl isosorbide(potent solvent) 10.00  10.00  10.00  Isopropyl myristate 5.60 5.60 5.60Glyceryl monostearate 0.45 0.45 0.45 Xanthan gum 0.25 0.25 0.25 MethocelK100M 0.25 0.25 0.25 Polysorbate 80 0.85 0.85 0.85 PEG-40 stearate 2.502.50 2.50 Sodium lauryl sulphate 0.40 0.40 0.40 Preservative 0.25 0.250.25 TEA to pH 5.5 to pH 5.5 to pH 5.5 Propane/Butane 8.00 8.00 8.00Purified water to 100.00 to 100.00 to 100.00 Notes: Depending on theseverity of the insect infestation and the target site, theconcentration of the permethrin can range between 0.1% and 10%.Depending on the severity of the insect infestation and the target site,the concentration of malathion can range between 0.1% and 5%. Dependingon the severity of the insect infestation and the target site, theconcentration of the pyrethroid extract can range between 0.1% and 10%.

Example 3

This example describes a foamable insecticide composition, containingpermethrin (1%), as “first insecticide” and star anise oil as “secondinsecticide.”

Foam G % w/w Permethrin (first insecticide) 1.00 Isopropyl myristate(potent solvent) 5.60 Star anise oil (second insecticide) 2.00 Glycerylmonostearate 0.45 Diisopropyl adipate 3.00 Xanthan gum 0.25 MethocelK100M 0.25 Polysorbate 80 0.85 PEG-40 stearate 2.50 Sodium laurylsulphate 0.40 Preservative 0.25 TEA to pH 5.5 Propane/Butane 8.00Purified water to 100.00

Example 4

This example describes a foamable insecticide composition, concurrentlycontaining permethrin (1%), malathion (0.5%) or pyrethrum extract(0.33%)+piperonyl butoxide (4%), as “first insecticide” and star aniseoil as “second insecticide”, with or without a potent solvent.

Foam H Foam I Foam J % w/w % w/w % w/w Permethrin (first insecticide)1.00 Malathion (first insecticide) 0.50 Pyrethrum extract (firstinsecticide) 0.33 Piperonyl butoxide (first insecticide) 4.00Diisopropyl adipate (potent solvent) 3.00 3.00 3.00 Dimethyl isosorbide(potent solvent) 10.00  10.00  10.00  Star anise oil (secondinsecticide) 2.00 2.00 2.00 Isopropyl myristate 5.60 5.60 5.60 Glycerylmonostearate 0.45 0.45 0.45 Xanthan gum 0.25 0.25 0.25 Methocel K100M0.25 0.25 0.25 Polysorbate 80 0.85 0.85 0.85 PEG-40 stearate 2.50 2.502.50 Sodium lauryl sulphate 0.40 0.40 0.40 Preservative 0.25 0.25 0.25TEA to pH 5.5 to pH 5.5 to pH 5.5 Propane/Butane 8.00 8.00 8.00 Purifiedwater to 100.00 to 100.00 to 100.00

Example 5

This example describes an insecticide composition concurrentlycontaining permethrin (1%), or malathion (0.5%), as “first insecticide”;star anise oil as “second insecticide”, with or without a potentsolvent.

Emulsion Emulsion Emulsion Emulsion I II III IV % w/w % w/w % w/w % w/wPermethrin (first 1.00 1.00 insecticide) Malathion (first 0.50 0.50insecticide) Mineral oil 5.60 Diisopropyl adipate 3.00 3.00 (potentsolvent) Dimethyl isosorbide 10.00  10.00  (potent solvent) Star aniseoil (second 2.00 2.00 2.00 2.00 insecticide) Isopropyl myristate 5.605.60 5.60 5.60 Glyceryl monostearate 0.45 0.45 0.45 0.45 Xanthan gum0.25 0.25 0.25 0.25 Methocel K100M 0.25 0.25 0.25 0.25 Polysorbate 800.85 0.85 0.85 0.85 PEG-40 stearate 2.50 2.50 2.50 2.50 Preservative0.25 0.25 0.25 0.25 TEA to pH 5.5 to pH 5.5 to pH 5.5 to pH 5.5 Purifiedwater to 100.00 to 100.00 to 100.00 to 100.00

Example 6

This example describes non-occlusive insecticide compositions containingpermethrin 5%.

PER 079 PER 091 Ingredient % w/w % w/w Permethrin 5.00 5.00 Mineral oilheavy 22.00 — Isopropyl myristate 11.00 — Benzyl alcohol 1.50 1.50Glyceryl monostearate 0.50 0.50 Ceteareth-20 3.30 3.30 Stearyl alcohol1.10 1.10 Purified water, 56.75 89.75 Carboxymethyl cellulose 0.55 0.55Glycerin 3.30 3.30 Total product: 100.00 100.00 Notes: Propellant wasadded to the above compositions at a concentration of 8%. The totalamount of hydrophobic carrier is in the range between 20% and 40%.

Example 7

This example describes additional insecticide compositions containingpermethrin 5%.

PER5-092 PER5-093 PER5-094 Ingredient Name % w/w % w/w % w/w Permethrin5.05 5.05 5.05 PPG 15 stearyl ether 15.00 — 12.00 Isopropyl myristate5.00 5.00 21.00 Benzyl alcohol 1.50 1.50 1.50 Glyceryl monostearate 0.500.50 1.00 Ceteareth-20 3.30 3.30 3.30 Stearyl alcohol 1.10 1.10 1.10Water, purified 62.70 62.70 51.20 Carboxymethyl cellulose 0.55 0.55 0.55Glycerin — — 3.30 Total product: 100.00 100.00 100.00

Example 8

This example describes an open study to assess the efficacy, safety andusability of a 1% permethrin foam containing a first insecticide, asecond insecticide and a potent solvent, in the treatment of head lice(pediculosis capitis) in pediatric patients.

Study Objectives:

1. To assess the efficacy and safety of a 1% Permethrin Foam, in thetreatment of head lice (pediculosis capitis) in pediatric patients2. To detect any side effects of the Foamix 1% Permethrin Foam.3. To assess the usability of the product.

Methodology:

-   -   The study was performed as a single center open study.    -   All patients' parents gave written informed consent to        participate in the study.    -   The test article, Foamix 1% Permethrin Foam, was applied by the        investigator, using an average quantity of 20 gram per patient,        according to hair type (length, thickness, curliness etc), on        wet or damp hair. The product penetrates under hair via        applicator connected to foam container. The foam was spread onto        hair through gentle rubbing in. The product remained in contact        with hair for 10 minutes and then was washed off with water and        a regular shampoo. The same procedure was repeated after 10        days.    -   24 hours after the first treatment, patients were examined for        lice visually and by 2-3 minutes combing. Lice and nits found        were counted and recorded.    -   Dermal side effects (itching, pain, irritation, etc), along with        any other adverse events were recorded throughout the study        period.

Number of Patients: 56 Diagnosis and Main Criteria for Inclusion:

Healthy male and female pediatric patients, 3 and 15 years of age,diagnosed as having pediculosis capitis.

Test Article: Foam H of Example 4. Dose: About 20 gr. Mode ofAdministration:

The treatment was performed by the Investigator or by one of the staffmember, under the Investigator's supervision an average quantity of 20gr. per patient, according to hair type (length, thickness, curliness,etc), on wet or damp hair (after a 2-3 minutes wash).

The product penetrates under hair via applicator connected to foamcontainer, as shown in the picture below.

The foam was spread onto hair through gentle rubbing in. The productremained in contact with hair for 10 minutes and then was washed offwith water and a usual shampoo. Treatment was repeated in 10 days.

In order to measure the applied amount of product, the foam containerwas weighed before and after every use.

Results and Conclusions: 1. Efficacy:

The product is found effective in lice killing in 96.4% of the patients.

The product further eradicated viable nits in 60% of the patients.

2. Safety:

No drug-related adverse effects were recorded.

3. Usability: A. Ease of Application.

-   -   Due to the nature a foam product, Foamix Permethrin 1% Foam was        found easier to use in comparison with other products available        in the market.    -   When foam is released it expands in the hair and reaches every        spot where lice can be found. This advantage is particularly        meaningful in regards to such difficult to access areas as in        the neck and behind the ears.    -   Using the product with applicator attached to foam container        directly onto the scalp under the hair is very convenient.

B. The Foam is Drip-Free

-   -   The foam is not liquid and therefore is not leaking when        applied.    -   This allows precise application, without the product being        spread on clothes or other parts of the body.    -   Not a single case of contact with eyes was recorded throughout        the study. (It should be noted that the issue of contact with        eyes is a common problem when treating with shampoo, lotion and        spray which usually cause eye irritation and burning.)

C. Patients' Response

-   -   Throughout the study it was evident that children enjoy being        treated with foam and therefore do not resist the therapy.

In conclusion, the present study provides evidence that Foam H ofExample 4 is safe and effective in the treatment of head lice(pediculosis capitis) in pediatric patients.

Example 9

This example describes a single-blind study of the transepidermal waterloss effect of PER 079 and PER 091 vehicle formulations from Example 6in subjects with normal skin in comparison with Petrolatum and NoTreatment.

Transepidermal water loss (TEWL) is often used to assess the occlusiveeffect of a composition. A single-blind study was carried out to assessthe effect of two principal vehicle formulations on TEWL, in comparisonwith petrolatum (positive control) and no treatment (negative control).Square areas of the same size, 4 cm2 each were drawn in the forearms.The areas were randomly assigned to a single treatment with one of thepreparations (PER 079, PER 091 or petrolatum) and one area remaineduntreated. 40 mg of each of the preparations were applied. The followingtable provides the TEWL values prior to treatment (baseline) and 30minutes afterwards.

No PER 079 PER 091 Petrolatum Treatment Mean SE Mean SE Mean SE Mean SEBaseline 3.8 0.4 3.8 0.5 3.8 0.5 4.1 0.5 30 min 3.4 0.3 3.6 0.3 1.7 0.23.8 0.4 % Change −10.5% −5.3% −54.3% −7.3%

The following conclusions had been recorded in light of the studyresults:

-   -   1. The positive control showed a significant decreased of 54.3%        in the TEWL values 30 minutes after application, thus confirming        that the experimental system responds to a positive control.    -   2. The negative control (no-treatment) remains stable with        negligible decrease of 7.3% after 30 minutes.    -   3. Formulations PER 079 and PER 091 showed a similar pattern of        TEWL change 30 minutes after treatment, with no significant        difference between formulations. There was no significant        difference in the TEWL change between formulations PER 079 and        PER 091 and the negative control.

Hence, it could be concluded that formulations PER 079 and PER 091 arenon-occlusive.

1. A foamable composition comprising: i. an active agent; ii. at leastone organic carrier selected from the group consisting of a hydrophobicorganic carrier, an organic polar solvent, an emollient and mixturesthereof, at a concentration of about 2% to about 50% by weight; iii. asurface active agent; iv. about 0.01% to about 5% by weight of at leastone polymeric agent selected from the group consisting of bioadhesiveagents, gelling agents, film forming agents and phase change agents andmixtures thereof; v. water; and vi. a liquefied or compressed gaspropellant at a concentration of about 3% to about 25% by weight of thetotal composition; wherein the composition is stored in a container andupon release it forms a breakable foam that collapses upon applicationof shear force; and wherein the composition includes less than 5% orabout 5% by weight of lower alcohols.
 2. The composition of claim 1,wherein the active agent is an insecticide.
 3. The composition of claim1, wherein the organic carrier is present at about 5% to about 50% byweight of the composition and the surface-active agent is present atabout 0.1% to about 5% by weight of the composition.
 4. The compositionof claim 1, wherein the composition is an emulsion.
 5. The compositionof claim 1, further including about 0.1% to about 5% by weight of a foamadjuvant.
 6. The composition of claim 2, wherein the insecticide isselected from the group consisting of an antibiotic insecticide, abotanical insecticide, a carbamate insecticide, a dinitrophenolinsecticide, a fluorine insecticide, an insect growth regulator, achitin synthesis inhibitor, a juvenile hormone mimics, a moultinghormone agonist, a moulting inhibitor, a nereistoxin analogueinsecticide, a nicotinoid insecticide, a pyridylmethylamine insecticide,an organochlorine insecticide, a cyclodiene insecticide, anorganophosphorus insecticide, an organophosphate insecticide, anorganothiophosphate insecticides, an aliphatic amide organothiophosphateinsecticide, an oxime organothiophosphate insecticide, a heterocyclicorganothiophosphate insecticide, a benzothiopyran organothiophosphateinsecticide, a benzotriazine organothiophosphate insecticide, anisoindole organothiophosphate insecticide, an isoxazoleorganothiophosphate insecticide, a pyrazolopyrimidineorganothiophosphate insecticide, a pyridine organothiophosphateinsecticide, a pyrimidine organothiophosphate insecticide, a quinoxalineorganothiophosphate insecticide, a thiadiazole organothiophosphateinsecticide, a triazole organothiophosphate insecticide, such asisazofos and triazophos; a phenyl organothiophosphate insecticides, aphosphonothioate insecticide, a phenyl ethylphosphonothioateinsecticide, a phenyl phenylphosphonothioate insecticide, aphosphoramidate insecticide, a phosphoramidothioate insecticide, aphosphorodiamide insecticide, an oxadiazine insecticide, a phthalimideinsecticide, a pyrazole insecticide, a pyrethroid insecticide, apyrethroid ester insecticide, a pyrethroid ether insecticide, apyrimidinamine insecticide, a pyrrole insecticide, a tetronic acidinsecticide, a thiourea insecticide and a urea insecticide.
 7. Thecomposition of claim 1, wherein the foamable composition comprises atleast one active agent selected from the group consisting of an asteroidal antiinflammatory agent, an immunosuppressive agent, animmunomodulator, an immunoregulating agent, a hormonal agent, anantibiotic agent, an antifungal agent, an antiviral agent, anantiparasitic agent, vitamin A, a vitamin A derivative, vitamin B, avitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, avitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, avitamin F derivative, vitamin K, a vitamin K derivative, a wound healingagent, a disinfectant, an anesthetic, an antiallergic agent, an alphahydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, aprotein, a peptide, a neuropeptide, a allergen, an immunogenicsubstance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylicacid, azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid,an antiproliferative agent, an anticancer agent, a photodynamic therapyagent, benzoyl chloride, calcium hypochlorite, magnesium hypochlorite,an anti-wrinkle agent, a radical scavenger, a metal, silver, a metaloxide, titanium dioxide, zinc oxide, zirconium oxide, iron oxide,silicone oxide, talc, carbon, an anti wrinkle agent, a skin whiteningagent, a skin protective agent, a masking agent, an anti-wart agent, arefatting agent, a lubricating agent and mixtures thereof.
 8. Thecomposition of claim 1, wherein the organic carrier comprises a potentsolvent selected from the group consisting of propylene glycol, hexyleneglycol, benzyl alcohol, terpene-ol and dimethyl isosorbide.
 9. Thecomposition of claim 1, wherein the surface active agent is non-ionic ora combination of non-ionic and ionic surface active agent, wherein theratio of non-ionic surface active agent to ionic surface active agent isabout 6:1 or greater than 6:1.
 10. The composition of claim 1, whereinthe organic carrier is a hydrophobic solvent and wherein the surfaceactive agent is present at a concentration of about 0.1% to about 5% byweight.
 11. A method of treating, alleviating or preventing a disordercomprising: administering topically to a surface having the disorder, afoamed composition comprising: i. an active agent; ii. at least oneorganic carrier selected from the group consisting of a hydrophobicorganic carrier, an organic polar solvent, an emollient and mixturesthereof, at a concentration of about 2% to about 50% by weight; iii. asurface active agent; iv. about 0.01% to about 5% by weight of at leastone polymeric agent selected from a bioadhesive agent, a gelling agent,a film forming agent and a phase change agent and mixtures thereof; v.water; and vi. a liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition, wherein the foamed composition is a breakable foam thatcollapses upon application of shear force; and wherein the compositionincludes less than 5% or about 5% by weight of lower alcohols.
 12. Themethod of claim 11, wherein the active agent is an insecticide.
 13. Themethod of claim 11, wherein the organic carrier is present at about 5%to about 50% by weight of the composition and the surface-active agentis present at about 0.1% to about 5% by weight of the composition. 14.The method of claim 11, wherein the emulsion is selected from the groupconsisting of an oil-in-water emulsion and a water-in-oil emulsion. 15.The method of claim 11, wherein the foamable composition furtherincludes about 0.1% to about 5% by weight of a foam adjuvant.
 16. Themethod of claim 12, wherein the insecticide is selected from the groupconsisting of an antibiotic insecticide, a botanical insecticide, acarbamate insecticide, a dinitrophenol insecticide, a fluorineinsecticide, an insect growth regulatora chitin synthesis inhibitor, ajuvenile hormone mimics, a moulting hormone agonist, a moultinginhibitor, a nereistoxin analogue insecticide, a nicotinoid insecticide,a pyridylmethylamine insecticide, an organochlorine insecticide, acyclodiene insecticide, an organophosphorus insecticide, anorganophosphate insecticide, an organothiophosphate insecticides, analiphatic amide organothiophosphate insecticide, an oximeorganothiophosphate insecticide, a heterocyclic organothiophosphateinsecticide, a benzothiopyran organothiophosphate insecticide, abenzotriazine organothiophosphate insecticide, an isoindoleorganothiophosphate insecticide, an isoxazole organothiophosphateinsecticide, a pyrazolopyrimidine organothiophosphate insecticide, apyridine organothiophosphate insecticide, a pyrimidineorganothiophosphate insecticide, a quinoxaline organothiophosphateinsecticide, a thiadiazole organothiophosphate insecticide, a triazoleorganothiophosphate insecticide, such as isazofos and triazophos; aphenyl organothiophosphate insecticides, a phosphonothioate insecticide,a phenyl ethylphosphonothioate insecticide, a phenylphenylphosphonothioate insecticide, a phosphoramidate insecticide, aphosphoramidothioate insecticide, a phosphorodiamide insecticide, anoxadiazine insecticide, a phthalimide insecticide, a pyrazoleinsecticide, a pyrethroid insecticide, a pyrethroid ester insecticide, apyrethroid ether insecticide, a pyrimidinamine insecticide, a pyrroleinsecticide, a tetronic acid insecticide, a thiourea insecticide and aurea insecticide.
 17. The method of claim 11, wherein the foamablecomposition comprises at least one active agent selected from the groupconsisting of an a steroidal antiinflammatory agent, animmunosuppressive agent, an immunomodulator, an immunoregulating agent,a hormonal agent, an antibiotic agent, an antifungal agent, an antiviralagent, an antiparasitic agent, vitamin A, a vitamin A derivative,vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative,vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative,vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, awound healing agent, a disinfectant, an anesthetic, an antiallergicagent, an alpha hydroxyl acid, lactic acid, glycolic acid, abeta-hydroxy acid, a protein, a peptide, a neuropeptide, a allergen, animmunogenic substance, a haptene, an oxidizing agent, an antioxidant, adicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaricacid, a retinoid, an antiproliferative agent, an anticancer agent, aphotodynamic therapy agent, benzoyl chloride, calcium hypochlorite,magnesium hypochlorite, an anti-wrinkle agent, a radical scavenger, ametal, silver, a metal oxide, titanium dioxide, zinc oxide, zirconiumoxide, iron oxide, silicone oxide, talc, carbon, an anti wrinkle agent,a skin whitening agent, a skin protective agent, a masking agent, ananti-wart agent, a refatting agent, a lubricating agent and mixturesthereof.
 18. The method of claim 11, wherein the organic carriercomprises a potent solvent selected from the group consisting ofpropylene glycol, hexylene glycol, benzyl alcohol, terpene-ol anddimethyl isosorbide.
 19. The method of claim 11, wherein the surfaceactive agent is non-ionic or a combination of non-ionic and ionicsurface active agent, wherein the ratio of non-ionic surface activeagent to ionic surface active agent is about 6:1 or greater than 6:1.20. A method of treating, alleviating or preventing a disordercomprising collapsing a breakable foam obtained by dispensing thefoamable composition of claim 1, by application of a mechanical force tothe breakable foam such that it is spread at or about a target site on asubject without irritation of the target site surface.